Journal
CANCER RESEARCH
Volume 78, Issue 1, Pages 256-264Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-0469
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Funding
- NIH National Institute of Neurological Disorders and Stroke [R01-NS06703]
- NCI [R01-CA134844]
- Department of Defense [W81XWH-10-1-0089]
- National Brain Tumor Society
- American Brain Tumor Association
- Accelerate Brain Cancer Cure Foundation
- Kinetics Foundation
- Ben and Catherine Ivy Foundation
- Duke University's Clinical & Translational Science Awards from the NIH National Center for Research Resources [1UL2 RR024128-01]
- NATIONAL CANCER INSTITUTE [F30CA196199, R01CA134844] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR024128] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007171] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS067037] Funding Source: NIH RePORTER
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Median survival for glioblastoma (GBM) remains < 15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8(+) T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8(+) T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination(CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFN gamma-, TNF alpha-, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8(+) T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study. (C) 2017 AACR.
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